Diabetes is generally characterized by relatively high levels of plasma glucose (hyperglycemia) in the fasting state. Type 2 diabetics can often develop insulin resistance, in which the effect of insulin in stimulating glucose and lipid metabolism is diminished. Further, patients who have developed insulin resistance, but not type 2 diabetes, are also at risk of developing Syndrome X (metabolic syndrome). Syndrome X is characterized by insulin resistance, along with obesity (e.g., abdominal obesity), hyperinsulinemia, high blood pressure, relatively low HDL and relatively high VLDL. Although current treatments for type 2 diabetes can result in reduced levels of blood sugar, side effects can include weight gain, hyperglycemia, edema, and liver toxicity.
Protein tyrosine phosphatase 1b (PTP1b), a ˜50 kd intracelluar PTPase abundant in various human tissues, has been studied for its potential role as a negative regulator of insulin signaling. Some studies have shown that PTP1b is a negative regulator of insulin signaling. For example, mice deficient in PTP1b were healthy and showed increased insulin sensitivity and resistance to diet-induced obesity. These mice had lower glucose, insulin and triglyceride levels as well as improved insulin sensitivity as measured by glucose and insulin tolerance tests. PTP1b has also been implicated in attenuation of leptin receptor signaling. PTP1b deficient mice were shown to be more sensitive to leptin, which may explain in part their resistance to weight gain when placed on a high fat diet. Thus, the main target tissues for PTP1b inhibition appear to be insulin action in muscle and liver, as well as leptin signaling in the brain, while the commercial diabetes drugs, the peroxisome proliferative activated receptor-gamma (PPAR-γ) agonist class of insulin sensitizers, target adipose tissue. Thus inhibition of PTP1b provides a target for regulating a variety of cellular responses important to human diseases related to obesity and type 2 diabetes.